The Interplay Between the Gut Microbiome and Immunotherapy in Gastrointestinal Malignancies: Mechanisms, Clinical Implications, And Therapeutic Potential

Background: The gut microbiome has emerged as a critical modulator of host immune responses, significantly influencing the efficacy of immunotherapy in gastrointestinal (GI) cancers, including colorectal carcinoma (CRC), gastric cancer (GC), and esophageal adenocarcinoma (EAC). Emerging evidence suggests that microbial dysbiosis can either potentiate or impede immune checkpoint inhibitors (ICIs), adoptive cell therapies, and cancer vaccines. Objective: This review synthesizes current knowledge on the bidirectional crosstalk between the gut microbiota and antitumor immunity, focusing on molecular mechanisms, preclinical models, and clinical trials evaluating microbiome-based interventions to enhance immunotherapy outcomes. Methods: A systematic literature review was conducted using PubMed, EMBASE, and Cochrane databases, prioritizing studies on fecal microbiota transplantation (FMT), probiotics, and microbial biomarkers predictive of immunotherapy response. Results: Specific commensal bacteria (e.g., Akkermansia muciniphila, Bifidobacterium spp., Faecalibacterium prausnitzii) are associated with improved ICI response via dendritic cell activation, CD8+ T-cell infiltration, and reduced regulatory T-cell (Treg) suppression. Conversely, antibiotic-induced microbiota depletion correlates with diminished pembrolizumab and nivolumab efficacy. Clinical trials testing FMT in refractory melanoma and CRC demonstrate restored therapeutic sensitivity, suggesting translatability to GI cancers. Conclusion: The gut microbiome represents a promising adjunctive target to optimize immunotherapy in GI oncology. Future research should standardize microbial manipulation strategies and validate predictive biomarkers for personalized treatment paradigms.